The LDL receptor-related protein (LRP) family is of interest in Alzheimer disease (AD) research because it includes several receptors for apolipoprotein E (ApoE), and polymorphisms in the gene for the latter (APOE) create the most demographically significant genetic risk factor for developing AD. Another genetic contribution is made by the genes for presenilins (PS)-1 and - 2; mutations in these genes are responsible for the largest fraction of early-onset AD inherited in an autosomal-dominant manner. Preliminary data indicate that such PS1 mutants reduce the steady-state levels of LRPs below what is seen with wild-type PS1. The proposed studies will characterize this relationship further and test the mechanisms involved and the consequences for LRP function. Successful completion of these studies will inform a novel hypothesis that places LRP dysfunction at a central point in the mechanisms common to AD pathogenesis.